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Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Genetic testing for cardiovascular disease is becoming common. For HCM, the diagnostic yield of testing is 60–70%; however, testing for DCM has a much lower yield. The most frequently identified gene is lamin A/C, but only when the disease is associated with AV block (with or without skeletal myopathy). In pure DCM, the yield screening for a large number of genes is about 20%. Truncating variants in TTN and DSP are most associated with DCM. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1 and VCL are significantly enriched in specific patient subsets, with the last two genes potentially contributing primarily to early-onset forms of DCM. Four major epigenetic modifications, DNA methylation, histone modification, chromatin remodelling, as well as the noncoding RNAs, have an influence on DCM phenotypic expression.
Bioinformatics analysis of the clinicopathological and prognostic significance of BAG3 mRNA in gynecological cancers
Published in Journal of Obstetrics and Gynaecology, 2023
Zi-mo Wang, Li Zhang, Dong-hui Ren, Cong-yu Zhang, Hua-chuan Zheng
Li et al. (2018) found that BAG3 regulates signalling pathways involved in CRC cell proliferation, migration, invasion, and chemoresistance. In our study, the top BAG3-related pathways included ligand-receptor interactions and activity, DNA packaging and nucleosomes, hormonal response, membrane regions, microdomains and rafts, and endosomes in breast cancer; ligand-receptor interactions, transmembrane transporters and channels, cell adhesion, and keratinisation in cervical cancer; ligand-receptor interactions, anion transmembrane transporters, lipoproteins, keratinisation, cell adhesion, and protein processing in endometrial cancer; metabolism of porphyrin, chlorophyll, pentose, uronic acid, ascorbate and alternate, and cell adhesion in ovarian cancer. These findings provide novel clues about the roles and molecular mechanisms by which BAG3 plays an important role in the tumorigenesis and progression of gynecological cancers, which should be investigated in future studies.
Novel Intragenic PAX6 Deletion in a Pedigree with Aniridia, Morbid Obesity, and Diabetes
Published in Current Eye Research, 2020
Erin A. Boese, Mallory R. Tollefson, Michael J. Schnieders, Benjamin W. Darbro, Wallace L.M. Alward, John H. Fingert
Genetic analyses were conducted to investigate the cause of the proband’s cardiomyopathy including a cytogenetics analysis at the University of Iowa and two commercial assays for mutations: a next-generation DNA sequencing assay to test for coding sequence defects, deletions, and duplications in a panel of 50 known cardiomyopathy genes: ABCC9, ACTC1, ACTN2, AGL, BAG3, CACNA1C, CAV3, CRYAB, CSRP3, DES, DMD, DOLK, DSC2, DSG2, DSP, EMD, EYA4, FHL1, FKRP, FKTN, FLNC, GAA, GLA, HCN4, JUP, LAMP2, LMNA, MYBPC3, MYH7, MYL2, MYL3, PKP2, PLN, PRKAG2, RAF1, RBM20, RYR2, SCN5A, SGCD, SLC22A5, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL (Invitae, San Francisco, CA) and Whole-Genome Oligonucleotide Array Comparative Genome Hybridization (CGH) assay to precisely map deletions and insertions (GeneDx, Gaithersburg, MD). The GRCh37 human genome build was used for the CGH analysis.
HIV Tat-mediated induction of autophagy regulates the disruption of ZO-1 in brain endothelial cells
Published in Tissue Barriers, 2020
Ke Liao, Fang Niu, Guoku Hu, Ming-Lei Guo, Susmita Sil, Shilpa Buch
Based on the above information, we thus hypothesized that exposure of HBMECs to Tat could lead to the induction of endothelial autophagy, which in turn, could contribute to the downregulated expression of tight junction proteins, ultimately resulting in the disruption of BBB. Our findings demonstrate the time-dependent induction of autophagy in HBMECs exposed to Tat. Increased autophagy, in turn, contributed to Tat-mediated downregulation of tight junction protein ZO-1, thereby increasing vascular permeability in our in vitro BBB model. We do acknowledge the limitation of our in vitro BBB model is that it comprises of a single cell type – HBMECs. Although brain microvascular endothelial cells are the major components of the BBB, many studies have included other cell types such as astrocytes, pericytes and neurons in their model system, all of which play crucial regulatory roles in the maintenance of the BBB.28 It is reported29 that the TEER values measured in vivo could reach as high as 5900 Ω.cm2 which is markedly greater than that achieved in our in vitro model (around 150 Ω.cm2). In our future studies will plan to use complex in vitro co-culture models involving other cell types. Next, we sought to examine the molecular mechanism(s) underlying this process. BECN1/Beclin-1 is a key component of class III phosphatidylinositol 3-kinase complex (PI3KC3) that initiates the formation of autophagosomes by facilitating the localization of other autophagy proteins to the pre-autophagosomal membrane.12 K63-linked ubiquitination of BECN1/Beclin-1 has been demonstrated to be required for the initiation of autophagosome formation.30 In our current study, we demonstrated a novel mechanism by which Tat triggered PELI1/K63-linked ubiquitination of BECN1/Beclin-1 resulting in the induction of autophagy with a concomitant downregulated the expression of tight junction proteins ZO-1, ultimately leading to increased vascular permeability. Our findings demonstrated the Tat-mediated induction of autophagosome formation with a concomitant down-regulated expression of SQSTM1 in HBMECs. These findings are in agreement with previous studies in glial cells demonstrating Tat-mediated induction of BAG3 proteins, subsequently leading to increased autophagy, as evidenced by an increase in MAP1LC3B expression and a decrease in SQSTM1.15 Reports in other cells such as the neurons by Hui et al.31 however, have reported that Tat (100 nM, 1.6 µg/ml) was associated with lysosomes resulting in reduced expression of MAP1LC3B. It is thus possible that Tat could exert differential effects in different cell types, and also that these effects could be dose-dependent.